PROJECT SUMMARY Sensory systems, including olfaction, are heavily dependent on signals from higher brain regions that regulate behavioral states of alertness and attention. A major center for these modulatory inputs is the basal forebrain. The basal forebrain (BF) sends axonal projections throughout the brain and has been implicated in dynamic modulation of cortical as well as sensory circuits during behavior. BF is classically thought of as a center for cholinergic projections throughout the brain, whose chief functional role is to mediate attentional modulation of information processing. However, the recent advent of novel tools for probing neural circuits in vivo has enabled a deeper and more nuanced understanding of basal forebrain organization and role in cognition. BF projections to neocortex are in fact neurochemically diverse and precisely organized with respect to projection target. Further, different BF subpopulations are linked to distinct aspects of behavior and are implicated in diverse cognitive functions including reward signaling, behavioral responding to sensory cues and task learning. Despite these advances, however, we still know little about BF impact on the initial processing of sensory inputs on their way to cortex. The olfactory bulb (OB) is advantageous for investigating basal forebrain function, as it is the only primary (pre-cortical) sensory processing area receiving BF inputs and because olfaction is a primary modality driving behavior in rodents. BF sends massive projections to the OB, with terminations in all OB layers. Many of these projections are cholinergic. However, as for neocortex, BF projections to OB are neurochemically diverse with substantial numbers of GABAergic neurons. The importance of this diversity has only recently begun to be appreciated for cortex, but almost entirely unexamined with respect to OB circuitry. A recent study showed that GABAergic basal forebrain projections to the olfactory bulb target distinct neuronal subpopulations and can, independent of cholinergic projections, modulate OB circuits to affect odor perception. However, our understanding of the respective roles played by BF cholinergic and GABAergic in modulating OB circuits and odor perception remains rudimentary. Fundamental unanswered questions include whether cholinergic and GABAergic basal forebrain projections target distinct components of olfactory bulb circuits, whether they have complementary or opposing effects on odor representations at the level of olfactory bulb output, what are the activity patterns of cholinergic and GABAergic basal forebrain neurons during behavior, and what role these projections play in odor perception or odor-guided behaviors? The overall goal of this proposal is to investigate how the basal forebrain neuromodulatory inputs affect olfactory bulb function in a multi-disciplinary study spanning investigation at the level of single neurons through to animal behavior utilizing advances in electrophysiology, opto-/pharmacogenetics, and high resolution activity imaging and microendcosopy in behaving animals.